Production of alpha, alpha-spiro-heptamethylene-succinic acid imides



I Zfillfil E Patented Nov. 3, 1959 rates Patent "'l 2 2911 412 pound, in which the double linkage is situated in the t ring, behaves in the reaction according to the present in PRODUCTION OFALPHA, ALPHA-SPIRO-HEPTA- vention as if the double linkage were situated outside the vMEYIHYLlENE-SU(ZCINI C ACID'IMIDES ring (S66 Formula l l s l and qtie-sehliehtihg; Ludwigshafell 5 The kind of alcohol radical in the cyclo-octylidene- G a y, asslgllels t0 Baq Amhh; & cyanoacetic acid ester (I) used as initial material is Withsoda'Fabnk Aktlengeseuschaftr Ludwlgshafe (Rhine)! out importance for the reaction according to this inven- Germany tion. The ester can be formed for example from a low N0 Drawihg- Application November 1957 molecular aliphatic alcohol, such as methyl, ethyl, propyl,

Sel'i3H 10.. isopropyl, butyl and isobutyl. Claims priority, application Germany November 10, 1956 As the alkali cyanide. there are chosen for practical reasons the readily accessible sodium or potassium salts 6 Claims. (Cl. 260-4265) of hydmcyanic acid This invention relates to new derivatives of cyclothe Strong ihellgallie e W Which the e p f octane d th i production, alpha-heptamethylene-succmodimtrile-beta-carboxylic acid The object of the invention is the production of alpha, ester t formed is heated, e 15 p e y used alpha-spiro-heptamethylenesuccinic a id imide sulfuric acid because the most favorable yields are A fu th bj t f th i ti i t id new achieved therewith. 50 to 70% sulfuric acid in general substances with valuable pharmacological properties. gives the best y For the P ther lhetl'lle- The objects of the invention are achieved by allowing tions are necessary as to what acids and what acid conalkali cyanide to act on a cyclo-octylidene-cyanoacetic centrations are to be used moreover for the saponification acid ester (I), heating the resultant alpha, alpha-heptas of the alpha, alpha-heptamethylenesuccinodinitrile-betamethylenesuccinic acid dinitrile-beta-carboxylic acid carboxylic acid ester. ester (II) with a strong inorganic acid, and subjecting In the formula given above the radical R is hydrogen the alpha, alpha-heptamethylenesuccinic acid (HI) thereif the anhydride (1V) is reacted with ammonia or urea. by formed by saponification and decarboxylation, after For the rcactionof the anhydride (IV) there may also conversion into its anhydride (IV) 'to, treatment with be used primary amines. Suitable amines are for example ammonia, urea or a primary amine to convert it into its low molecular aliphatic amines with l to 8 carbon atoms. irnide. The carbon radical can contain double linkages or triple In the said manner there are obtained compounds of linkages. 'They can be branched or straight. There may the general fermulai be mentioned for example methylamine, ethylamine, CHFOH, propylamine, butylamine, allylamine. The carbon radical i can also in turn contain other radicals, as for example 043112-00 hydroxyl groups. Thus ethanolamine is also suitable as H10 CH1 a primary amine. The carbon radical can also be cyclo- CHZ-{HIIZ aliphatic, as is the case for example in cyclohexylamine.

Aromatic primary amines, if desired with further substituents on the aromatic ring can also be used, for example halogen-anilines, ethoxy-anilines and nitro-anilines. The primary amines can also bear heterocyclic radicals, so that aminopyridines are also suitable. The primary in which R can have the significance given further below.

The sequence of reaction according to "this invention can be formulated as follows in the case of the use of 40 cyclo-octylidene-cyanoacetic.acid ethyl. ester, potassium cyanide and methylamine as initial materials:

CN ON ON on COOC2H5 acid COOOzH I II lsaponification CONCH; GO-O 00011 CHaNH: H,o H 011 O 1:13-26 OH -OO t- H GHQ-*COOH IV III .amines enumerated are merely some of the possibilities. The cyclo-octylidene-cyanoacetic. acid esters serving as Many other primary amines can also be used in the initial materials are readily obtainable by condensation process of this invention. The radical which is situated 0f eyele-eetanohe With eyallofleetie acid estefsy on the nitrogen atom of theamino group corresponds to m y be ain for X mpl r ng o he irec i n the radical R in the above mentioned general formula. .ofthe German patent specification No. 925,168 (US. -\Allowing the alkali cyanide to act on the oyclo-octylpatent specification No; 2,744,900 and British patent idene-cyanoacetic acid ester (I) is possible for example specification No. 756,471). -by allowing cyclo-octylidene-cyanoacetic acid ester (I) According to these directions, starting from cycloin aqueous-alcoholic solution to stand together with octanone, it is heated in; glacial acetic acid solution with alkali cyanide for several hours at room temperature. a cyanoacetic acidmester, preferably in the presence of The reaction of the alkali cyanide with the cyclo-octylacetamide, formamide, :piperidine or: sodium acetate. idene-cyanoacetic acid ester proceeds more rapidly when After distilling off the glacial acetic acid together with the aqueous-alcoholic solution is heated. It is preferable the Water of reaction formed, the desired initial material to use an excess amount of alkali cyanide, for example =-is-obtained. Inthe-lsaid -literature.itisadesignatedtas ..1.5..to 2.5 mols, with reference to cyclo-octylidene-cyano- Al.Z-cyclo-octenyl-cyanoacetic acid ester. This comacetic acid ester (1). The expert will have no difiiculty in recognising the end of the reaction. Depending on the temperature at which the alkali cyanide acts on the cyclooctylidene-cyanoacetic acid ester (I) the reaction ends earlier or later. For example it lasts 48 hours at 4 of sulfuric acid and water which is four to five times that of the substance (II) to be saponificd. The time which is necessary for conversion of the compound H into the compound III amounts to about 8 to 9 hours but depends to C., 12 hours at to C., 5 hours at to 5 in detail on the temperature and the concentration of the C., 15 minutes at to C. Instead of a mixture sulfuric acid.

of water with ethyl alcohol, there can also be used mix- There are other possibilities of converting the comtures of water with other water soluble organic solvents, pound II by saponification and decarboxylation into the for example methanol, acetone, dioxane or tetrahydrocompound III, for example according to the Journal of furane. 10 Organic Chemistry, volume 15 (1950), page 381: by heatester can be recovered from this alkali metal compound 15 by acidification.

The alpha, alpha-heptamethylenesuccinodinitrile-betacarboxylic acid ester (II) or its alkali derivative is then heated under reflux in the presence of acid. Carbon diing for several hours under reflux With sulfuric acid in glacial acetic acid at about 120 C. and then heating for several hours with about 20% caustic potash solution at about C.

The alpha, alpha-heptamethylene-succinic acid is then preferably isolated in the way familiar to any expert and converted into the anhydride (IV). The anhydride can be obtained for example by heating the acid and, if desired, reduced pressure may be used. There may addioxide is split oif by the heating. When the splitting oif 20 tionally or solely also be used agents for splitting off of carbon dioxide ceases, the alpha, alpha-heptamethylene-succinic acid (III) has been formed from (II) by saponification and decarboxylation. The expert will have no diificulty in finding a suitable concentration of, for

water, as for example acetyl chloride, acetic anhydride or phosphorus oxychloride, in order to convert the acid (III) into the anhydride (IV). For the production of the anhydride also, the expert needs no detailed instrucexample, sulfuric acid, a suitable heating temperature 25 tions in each case because he will be quite familiar with and a suitable duration of heating in order to obtain the best possible yields in the conversion of compound II into compound III. For example the saponification and decarboxylation of the dinitrile when using 62% sulfuric the measures necessary for the purpose.

By reacting the anhydride (IV) in the cold with ammonia or a primary amine, there is in general first obtained an amide acid. This changes into the imide by acid and heating to an internal temperature of 140 C., 30 heating, for example to 150 to 200 C. at reduced presare ended after about 8 hours. Other concentrations and temperatures may also be used, for example C. with 50% sulfuric acid, C. with 55% sulfuric acid, to C. with 60 to 70% sulfuric acid. Highly sure, or by heating with agents which split off water, such as acetyl chloride or acetic anhydride. The imide can however be obtained directly from the anhydride by melting for example alpha, alpha-spire-heptamethyleneconcentrated sulfuric acid is not recommended because 35 succinic acid anhydride (IV) with urea at elevated temit is well known that this can destroy organic substances especially at high temperatures. For the success of the saponification of the dinitrile and the decarboxylation it is immaterial what amounts of acid are used. In genperatures. Temperatures between 130 and 160 C. are suitable for example.

The new compounds obtainable according to this invention are some of them crystalline and some are liquid.

eral however we use an amount by weight of the mixture 40 They have good anti-epileptic, and antispasmodic (i.e.

Protective Protective Toxicity mice dosage against dosage against p.o., mgJkg. cardiazol electrocramp,

cramp, mgJkg. mgJkg.

C O-NH about 1,400 about about 100.

C 0-N-GH;

more than2,000.. about 400 more than 400.

C O-NC Hp more than 2,000.. more than 400. about 150.

CHr- O C O-NH L about 1,400 more than 400- more than 400. CHr' O C O-NH about 150....-.-.- more than 100. more than 100.

C 0-NH about 1,000 about 400.--.-- about 150.

CH:- O

The protective dosage against electrocramp is deter-.

mined according to the method: Maximal electroshock assay, Toman, Swinyard and Goodman, Journal of Neurophysiology, 9, 231 (1946).

The protective dosage against cardiazol cramp is determined according to the method: anti-metrazol assay, Everett and Richards, Journal of Pharmacology and Experimental Therapeutics, 81, 402 (1944).

The following examples will further illustrate this invention but the invention is not restricted to these examples or the special measures described therein. The parts specified in the examples are parts by weight.

Example 1 A solution of 130 parts of potassium cyanide in 260 parts of water is added to a solution of 220 parts of cyclooctylidene-cyanoacetic acid ethyl ester in 880 parts of ethyl alcohol and the mixture allowed to stand for 48 hours at 20 to 25 C. After distilling oil the alcohol in vacuo, adding water and acidifying with dilute hydrochloric acid, the oil which separates is taken up in benzene and after distilling oif the same there are obtained 245 parts of crude alpha, alp-ha-heptamethylene-succinodinitrile-beta-carboxylic acid ethyl ester.

This product is heated for 8 hours with an about 62% sulphuric acid (prepared from 965 parts of concentrated sulphuric acid and 530 parts of Water) under reflux at an internal temperature of about 140 C. After cooling, it is poured onto ice and the precipitated crude acid is filtered off by suction. By dissolving it in hot sodium carbonate solution, filtering and precipitating with about 17% hydrochloric acid, 190 parts of alpha, alpha-heptamethylene-succinic acid of the melting point 155 to 156 C. are obtained. Recrystallised from 10% acetic :acid, it melts at 157 C.

380 parts of acetyl chloride are added to the alpha, :alpha-heptamethylene-succinic acid and the whole heated for 45 minutes under reflux. After distilling off the excess acetyl chloride, 157 parts of alpha, alpha-spiro-hep- 'tamethylene-succinic acid anhydride are obtained which boils at 130 to 132 C. at 0.3 Torr pressure.

38 parts of the anhydride thus obtained are mixed with 13 parts of urea and heated to 160 C. After the reaction has died away, the whole is kept at the said temperature for another half an hour and the melt then poured into cold water. The deposited precipitate is filtered off by suction, dried and recrystallised from xylene. 34 parts of alpha, alpha-spiro heptamethylene-succinimide of the melting point 142 to 143 C. are obtained. Its formula is:

H OHr-CO Instead of the 220 parts of cyclo-octylidene-cyanoacetic acid ethyl ester specified in paragraph 1 of this example, 235 parts of the propyl ester or 249 parts of the butyl ester may be used with the same result.

Example 2 220 parts of cyclo-octylidene-cyanoacetic acid methyl ester are dissolved in 320 parts of methanol. A solution of 130 parts of potassium cyanide in 400 parts of water is added and the mixture heated under reflux to boiling for 15 minutes. Then the further procedure of Example 1 is followed up to the recovery of the alpha, alpha-spiroheptamethylene-succinic acid anhydride.

parts of this anhydride are dissolved in 87 parts of dry benzene, 23 parts of normal-butylamine are added and the whole heated to boiling unde reflux for 1 hour. By distilling off the benzene at reduced pressure there are obtained 52 parts of the half-nonnal-butylimide of alpha, alpha-heptamethylene-succinic acid which after recrystallisation from dilute alcohol melts at 125 to 126 C.

By heating for 2 hours with 104 parts of acetyl chloride under reflux and subsequently distilling off the excess acetyl chloride, there are obtained therefrom 39 parts of alpha, alpha-spiro-heptamethylene-succinic acid N-normal-butylimide which boils at 124 to 128 C. under 0.2 Torr pressure.

OHg- O In a corresponding way from 38 parts of alpha, alphaspiro-heptamethylene-succinic acid anhydride by reaction with 38 parts of meta-chloraniline in 165 parts of benzene, there are obtained 60 parts of the half-metachloranilide of alpha, alpha-heptamethylene-succinic acid of the melting point 167 to 168 C. and therefrom 46 parts of alpha, alpha-spiro-heptamethylene-succinic acid N-meta-chlorphenylimide of the melting point 116 C.

(from cyclohexane) OO-III 0112-00 1 Example 3 39 parts of alpha, alpha-spiro-heptamethylene-succinic acid anhydride prepared as in the foregoing examples are heated in 150 parts of dry benzene with 20 parts of Z-aminopyridine for 1 hour to boiling under reflux. Upon cooling, 50 parts of the half-(pyridyl-(2)-) amide of alpha, alpha-heptamethylene-succinic acid crystallise out; its melting point after recrystallisation from normal-bu tanol is 158 C. I

This product is heated to 160 to 170 C. under reduced pressure until, after about 2 hours, no further water is split off. The melt, which solidifies after cooling, is recrystallised from cyclohexane. 40 parts of alpha, alphaspiro-heptamethylene-succinic acid N-(2-pyridyl)-imide of the melting point to 106 C. are obtained. The hydrochloride prepared therefrom in the usual way melts at to 156 C.

Lifer-l0 By reacting 5 8 parts of the anhydride with 21 parts of ethanolamine there can be obtained by the same method I of operation, 57 parts of the corresponding N-(beta-hydroxyethyD-irnide of the melting point 47 to 48 C.

C O-NC HrCH z--OH @Cal.

@OHHLO Example 4 Gaseous methylarnine is led while cooling into a solution of 40 parts of alpha, alpha-spiro-heptarnethylenesuccinic acid anhydride prepared as in Example 1 in 525 parts of absolute ether until saturation is reached. The whole is then evaporated to dryness, the residue dissolved in dilute sodium carbonate solution and the half-methylamide of alpha, alpha-heptamethylene-succinic acid formed precipitated with dilute hydrochloric acid. It melts at 144 to 145 C.

38 parts of this half-methylamide are heated to boiling with 76 parts of acetyl chloride for 2 hours under reflux. After evaporating the acetyl chloride there remain behind 30 parts of alpha, alpha-spiro-heptamethylenesuccinic acid N-methylimide of the boiling point 134 C. under 0.5 Torr:

CO-N-OH;

@Cal...

CHg-CH: CO-N-H HaC C-OHz-O 2. A compound of the general formula wherein R is the hydroxy ethyl radical.

3. A compound-of the general formula /CH CH2 CONR mo (|JGH 0 H3O CH2 CHr-CH:

wherein R stands for para-ethoxy phenyl. 4. A compound of the general formula wherein R stands for a meta chloro phenyl.

5. The compound of the formula /CH;CH2 CO-N-CH; H2O (II-CH7- 0 HQC CH:

CH CH 6. A compound of the general formula /CH;CH CON(R),.H H1O |3-0H oo H1O /CH2 CH2-OH2 wherein It stands for one of the figures 0 and 1 and R is a member selected from the group consisting of the divalent radical CH CH -CH --CH -CH O, CH CH=CH-- CH -CH CH CH CH CH CH Miller et al.: J. Amer. Chem. Soc., vol. 73, pp. 4895- 4898 (1951).

Cragoe et al.: J. Org. Chem, vol. 15 (1950), p. 381.

Desai et al.: Chemical Abstracts, vol. 35 (1941), p. 6934. 

1. A COMPOUND OF THE GENERAL FORMULA
 6. A COMPOUND OF THE GENERAL FORMULA 